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| United States Patent |
6,153,221
|
|
Thut
, et al.
|
November 28, 2000
|
Use of biogically active glass as a drug delivery system
Abstract
This invention relates to a synthetic bone replacement material impregnated
with drugs such as antibiotics and growth hormones, which facilitate and
promote the regeneration of bone and/or soft tissue. Methods for making
the impregnated material and its medical use are also taught.
| Inventors:
|
Thut; Paul D. (6309 Blenheim Rd., Baltimore, MD 21212);
Litkowski; Leonard J. (621 Sussex Rd., Towson, MD 21286);
Greenspan; David C. (Gainesville, FL)
|
| Assignee:
|
Thut; Paul D. (Baltimore, MD);
Litkowski; Leonard J. (Towson, MD)
|
| Appl. No.:
|
157636 |
| Filed:
|
September 21, 1998 |
| Current U.S. Class: |
424/484; 424/423 |
| Intern'l Class: |
A61K 009/10; A61K 009/14 |
| Field of Search: |
424/400,423,489,486,484
514/951,953,964-65,769-770
|
References Cited
U.S. Patent Documents
| 4103002 | Jul., 1978 | Hench et al.
| |
| 4138325 | Feb., 1980 | Barrett et al.
| |
| 4159358 | Jun., 1979 | Hench et al.
| |
| 4171544 | Oct., 1979 | Hench et al.
| |
| 4218255 | Aug., 1980 | Bajpai et al.
| |
| 4234972 | Nov., 1980 | Hench et al.
| |
| 4775646 | Oct., 1988 | Hench et al.
| |
| 4851046 | Jul., 1989 | Low et al.
| |
| 5074916 | Dec., 1991 | Hench et al.
| |
| 5262166 | Nov., 1993 | Liu et al.
| |
| 5294446 | Mar., 1994 | Schlameus et al.
| |
| 5591453 | Jan., 1997 | Ducheyne et al.
| |
| 5626861 | May., 1997 | Laurencin et al.
| |
| 5643789 | Jul., 1997 | Ducheyne et al.
| |
| 5648301 | Jul., 1997 | Ducheyne et al.
| |
| Foreign Patent Documents |
| US95/09401 | Jul., 1995 | WO.
| |
Other References
Hench, L. L. et al., "Direct chemical Bond of Bioactive Glass-Ceramic
Materials to Bone and Muscle." J. Biomed. Mater. Res. Sym., No. 4, p.
25-42 (1973).
Hench, L. L. et al., "Bonding Mechanisms at the Interface of Ceramic
Prosthetic Materials." J. Biomed. Mater. Res. Sym., No. 2 (part 1)
p.117-141 (1971).
Wilson, J. et al., "Biomaterials for facial bone augmentation: Comparative
studies." J. Biomed. Mate. Res., vol. 22, No. A2, p159-177 (1988).
Wilson, J. et al., "Toxicology and biocompatibility of bioglasses." J.
Biomed. Mater. Res., vol. 15, p805-817 (1981).
Bentia, S., "Microencapsulation: Methods and Industrial Application."
Marcel Dekker, Inc., 1996.
Otsuka, M., et al., "New Skeletal Drug Delivery system Containing
Antibiotics Using Self-Setting Bioactive Glass Cement", Chem. Pharm.
Bull., 40(12): 3346-3348, 1992.
Otsuka, M., et al., "A Novel Skeletal Drug Delivery System for Antibiotic
Drugs using Self-Setting Bioactive Bone Cement Based on CaO-SiO.sub.2
-P.sub.2 0.sub.5 Glass", Bioceramics, 5: 241-248, 1992.
Wilson, J., et al., "Bioactive Materials For Periodontal Treatment: A
Comparative Study", Biomaterials and Clinical Application, 223-228, 1987.
|
Primary Examiner: Webman; Edward J.
Attorney, Agent or Firm: Burns, Doane, Swecker & Mathis, L.L.P.
Parent Case Text
This application is a divisional of application Ser. No. 08/940,393, filed
Oct. 1, 1997 now U.S. Pat. No. 5,972,384.
Claims
What is claimed is:
1. A method for promoting the regeneration of missing or damaged bone
tissue in a mammal comprising replacing the missing or damaged bone tissue
with biologically active, ceramic-glass material impregnated with at least
one beneficial, physiologically active drug in microencapsulated form,
capable of releasing the agent at a predetermined rate when placed in a
physiological environment.
2. The method of claim 1 wherein the beneficial drug is selected from the
group consisting of antibiotics, analgesics, local anesthetics, 17-.beta.
estradiols, bone morphogenetic proteins, anti-epileptics, endocrine
hormones, cytokines, interleukins leukotrienes, calcitonin, transforming
growth factors-.beta., interferons, corticols, non-steroidal
anti-inflammatory drugs, interlukins 3 inhibitors and growth hormones.
3. The method of claim 1 wherein the beneficial drug is one or more
antibiotics and one or more growth hormones.
4. The method of claim 1 wherein the beneficial drug is microencapsulated
as microspheres.
5. The method of claim 1 wherein the biologically active, ceramic-glass
material has the following composition of component compounds:
______________________________________
Compound % Compound %
______________________________________
SiO.sub.2 40-60 CaF.sub.2 0-25
CaO 10-30 B.sub.2 O.sub.3
0-10
Na.sub.2 O 10-35 K.sub.2 O 0-8
P.sub.2 O.sub.5
2-8 MgO 0-5
______________________________________
with the proviso that the sum of the percentage of the component compounds
equals 100%.
6. The method of claim 5 wherein the biologically active ceramic-glass
material has the following composition of component compounds:
______________________________________
Compound
%
______________________________________
SiO.sub.2
45.0
CaO 24.5
Na.sub.2 O
24.5
P.sub.2 O.sub.5
6.0.
______________________________________
7. The method of claim 1 wherein the predetermined rate is substantially a
uniform rate.
Description
The present invention relates to a particulate, biologically active
ceramic-glass material in conjunction with one or more therapeutically
beneficial micro-encapsulated drugs and its use as a means for the
controlled delivery of the drugs into the body of a mammal in need
thereof.
BACKGROUND OF THE INVENTION
A drug may be administered to a patient systemically or locally. When a
drug is administered systemically, it enters the circulatory system, i.e.,
the blood stream, travels throughout the body, and hopefully, an effective
amount of the drug will reach the part of the patient's body in need of
treatment before the drug is degraded by metabolism and excreted.
Typically, a drug is taken orally in the form of a syrup, tablet, capsule
and the like, passes through the stomach then into the intestines where it
passes through the intestine walls into the blood stream. Alternatively,
the drug may be injected directly into the blood stream or into soft
tissue where it diffuses into the blood stream.
In recent years, drugs have also been administered systemically by
transdermal delivery. That is, the drug is placed on the skin (typically
the drug is incorporated into a patch) and allowed to diffuse through the
skin to enter the blood stream. In a variation of this form of
administration, a drug formulation in a metabolizable matrix or a
container is implanted under the skin where the drug is slowly released
and finds its way into the patient's blood stream. This form of drug
delivery is particularly advantageous when a continuous, constant, low
level of drug is desirable. For example, this method is currently being
used to administer small amounts of nicotine to help patients stop
smoking, and to deliver a birth control drug over several weeks.
Topical administration is the most common form of local drug delivery.
Typically a drug containing formulation is placed directly on the area of
the body needing the drug. For example, an antibiotic in the form of a
cream or ointment may be spread onto an injured area of the skin, or a
drug in the form of an aerosol may be sprayed onto an inflamed mucus
membrane. Drugs may also be locally administered by injection. For
example, a dentist may inject an anesthetic into a patient's gums to
deaden the pain of a tooth extraction.
Often systemic delivery of a drug is inefficient because only a small
amount of the administered dose reaches its site of therapeutic action. In
many cases, especially where the toxicity of the drug is low, this
inefficiency may be off set by giving the patient a large enough dose of
the drug to compensate for its loss while it travels through the patient's
body. In some cases, local drug delivery is very difficult, if not
impossible, leaving systemic administration as the only viable
alternative. For example, if the patient is in need of an antipsychotic
drug, injection directly into the brain would not be considered. Perhaps
the biggest problem with systemic delivery is that a drug can enter parts
of the body where it can actually do harm or produce a noxious side
effect.
Since the early days of modern medicine, physicians have sought to replace
damaged bone tissue with an artificial material. In many cases the goal
has been not merely to replace the bone with a prothesis, but to provide a
matrix upon which new bone tissue could grow. Of course, such a
replacement material must be essentially nontoxic and nonallergenic,
relatively stable in physiologic environments, and mechanically strong,
but it should also bind to living tissue. Many polymeric and noble metal
materials have been used as bone replacement materials with limited
success rates. Generally, living tissue does not bind well, if at all,
with these relatively inert materials, which has limited their successful
use.
In recent years, more biologically active, "bioactive," materials have been
developed to which living bone tissue binds well. In particular, certain
inorganic, that is, ceramic, glass and ceramic-glass, materials with
relatively high bioactivity are now available. These inorganic materials
can be made with a porous structure which supports new bone tissue.
Ideally, the living tissue grows on and into the replacement material to
ultimately incorporate the material into a new bone structure. See U.S.
Pat. Nos. 4,159,358; 4,234,972; 4,103,002; 4,189,325; 34,171,544;
4,775,646; 4,857,046; and 5,074,916 (all incorporated herein by reference)
for information on ceramic-glass bioactive materials.
These bioactive materials have been shown to develop a strong bond with
hard tissue because of a series of ion exchange reactions between the
implant surface and body fluids that result in the formation of a
biologically active calcium phosphate film at the implant tissue
interface. See Hench et al, J. Biomed. Mater. Res., Vol. 5, pp. 117-141
(1971), and Hench et al, J. Biomed. Mater. Res., Vol. 7, pp. 25-42 (1973).
Bio-active glasses have also been shown to form firm bonds with soft
tissue. See Wilson, et al, J. Biomed. Mater. Res., Vol. 15, pp. 805-817
(1981); Wilson and Merwin, J. Biomed. Mater. Res.: Applied Biomaterials,
Vol. 22, No. A2, pp. 159-177 (1988); and Wilson, Low et al, Biomaterials
and Clinical Applications, Ed. By Pizzoferrato et al, Elsevier Science
Publishers B.V., Amsterdam (1987). Many of these inorganic materials are
biodegraded at a slow rate, so that in time, the replacement material
disappears leaving natural bone structure in its place.
In conjunction with implantation of biologically active materials,
parenteral or oral administration of beneficial drugs, e.g., antibiotics,
hormones, and hormone-like material, have been demonstrated to enhance
formation of new bone and to prevent infection, with varying degrees of
success. However, the systemic delivery of such drugs results in
distribution of the drugs to sites where their effects are not required
and where they may do harm. Further, local administration has been
difficult and not practical.
The physical mixing of antibiotic drugs either in free drug form (Otsuka,
et al. Bioceramics, 5, 241 (1992)) or in the form of pulverized binder
containing antibiotic tablets with the bone substitute, results in uneven
biological activity and nonuniform release (Otsuka, et al. Chem. Pharm.
Bull., 40, 3346 (1992)). In particular, in cases where a drug has been
uniformly mixed with ceramic-glass and implanted to form a matrix onto
which new bone can grow (for example see, U.S. Pat. No. 5,591,453), the
concentration of the drug rapidly rises to a therapeutic range.
Unfortunately, the concentration of the drug continues to rise, exceeding
the therapeutic range and entering the potentially toxic range. As
metabolism and diffusion take effect, the concentration of the drug drops
back into the therapeutic range but continues to drop. The concentration
of the drug rapidly becomes sub-optimal and its therapeutic benefit is
lost. Although there are no reports of a hormone being mixed directly with
ceramic glass in lieu of an antibiotic drug, it is logical that the
changes in hormone level would follow a similar pattern.
The object of the present invention is to provide a particulate,
biologically active ceramic-glass impregnated with one or more
therapeutically beneficial drugs in a microencapsulated form and capable
of releasing the drugs at a controlled, predetermined rate. The
ceramic-glass may act as a bone substitute or a depot for the
therapeutically beneficial drugs to be released for systemic or local
treatment.
SUMMARY OF THE INVENTION
An aspect of the present invention is a particulate, biologically active,
ceramic-glass material in conjunction with one or more microencapsulated
therapeutically beneficial drugs, capable of releasing the drugs at a
predetermined rate when placed in a physiological environment, either in
bone or soft tissue. This impregnated biologically active, ceramic-glass
material is referred to as "ceramodrug matrix".
A second aspect of the present invention is a method for preparing the
ceramodrug matrix of the first aspect comprising the following sequential
steps:
a) Forming one or more drugs into biodegradable micro capsules which
degrade in physiological fluids at a pH level higher than about 7,
b) Forming a colloidal suspension of the biologically active, ceramic-glass
material by mixing the finely divided biologically active, ceramic-glass
material in one or more solvents, optionally void of suspending agent,
c) Stirring the micro capsules prepared in step a with the colloidal
suspension prepared in step b to yield a cosuspension of micro capsules of
drug and the biologically active, ceramic-glass, and
d) Removing the solvent in a sequential manner from the suspension formed
in step c yielding a ceramodrug matrix.
A third aspect of the present invention is a method for promoting the
regeneration of missing or damaged bone tissue in a mammal comprising
replacing the missing or damaged bone tissue with ceramic-glass bone
replacement material, impregnated with at least one therapeutically
beneficial drug in microencapsulated form, capable of releasing the drug
at a predetermined rate when placed in a physiological environment.
A fourth aspect of the present invention is a method for the controlled
release of therapeutically beneficial drugs into the bone or soft tissue
of a mammal in need of such drugs by placing ceramic-glass material,
impregnated with at least one therapeutically beneficial drug in
microencapsulated form, capable of releasing the drug at a predetermined
rate when placed in a physiological environment into the bone or soft
tissue of the mammal.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a graph showing the dramatic variation in the tissue
concentration of drug released by a ceramodrug matrix as a function of
time where the drug is simply mechanically mixed with a biologically
active, ceramic-glass.
FIG. 2 is a graph showing tissue concentration of drug released by a
ceramodrug matrix as a function of time where the drug is adsorbed onto
ceramic-glass.
FIG. 3a is a schematic diagram showing a microencapsulated drug in a
ceramodrug matrix filling a cavity within a bone, such that only the
surface is exposed to biological fluids.
FIG. 3b is a graph showing three variations of tissue concentration of a
drug released by a ceramodrug matrix as a function of time where the drug
is microencapsulated and distributed among the particles of the
biologically active, ceramic-glass matrix but certain conditions are
varied.
FIG. 4a is a schematic diagram similar to that of FIG. 3a but with multiple
drugs distributed in a ceramodrug matrix in gradients.
FIG. 4b is a graph showing tissue concentration of multiple drugs released
by a ceramodrug matrix as a function of time where each drug in the
ceramodrug matrix is microencapsulated, according to the diagram of FIG.
4a.
DETAILED DESCRIPTION OF THE INVENTION
As used herein the term "drug" has its usual meaning and includes, but is
not limited to, analgesics, local anesthetics, antibiotics, steroids,
anti-tumor agents, hormones, and hormone-like agents. "Bone replacement
material" is a substance that fills space left when bone is remove by
injury or surgery, which aids in forming an adhesion between adjacent
healthy bone and which is replaced by osteoblasts during the bone healing
and remodeling process, and, as used herein, is synonymous with "bone
matrix material." The terms "biologically active ceramic," "biologically
active glass," and "biologically active ceramic-glass" refer to inorganic
material containing an oxide of silicon as the predominate component which
is altered slowly by tissue fluids and which is remodeled during formation
of new bone.
As used herein the terms "microencapsulate" and "micro capsules" refer to
solid, colloidal, or liquid drug contained within a coating of a material
which dissolves or degrades in a physiological environment. The micro
capsules taught herein have a size greater than about 10 .mu.M and less
than about 1000 .mu.M. The term "micro spheres" as used herein means a
form of micro capsules of approximate sphere-shaped particles of a solid
matrix into which is embedded drug substances.
As used herein the term "ceramodrug matrix" means a composition comprising
particles, micro capsules, or microspheres of one or more drugs
distributed among the particles of the biologically active,
ceramic-glasses.
Referring to the graph of FIG. 1, if a finely divided drug intimately mixed
with a finely divided biologically active, ceramic-glass to form a
ceramodrug matrix is placed in bone or soft tissue, the concentration of
the drug in the surrounding tissue rapidly rises as biologic fluids
dissolve and distribute the drug as a function of time. The concentration
quickly reaches the therapeutic range (cross hatched area in FIG. 1) and
continues to rise through the super therapeutic range and into the
potentially toxic range. As the body metabolizes the drug, the level drops
over a short time, passing back through the therapeutic range, but quickly
entering the ineffective sub therapeutic range. This profile of drug
delivery might be used where it is important to deliver a burst of drug
over a short period. However, this profile would not generally be
preferred, and for some drugs a sudden, high concentration could be toxic
to the tissue.
FIG. 2 illustrates the preferred delivery profile for most drugs. The
concentration in the surrounding tissue rapidly rises to a level within
the therapeutic range and that level is maintained until all the drug in
the depot has been delivered. One means to achieve this profile, is to
adsorb the drug onto a divided particulate, ceramic-glass matrix. As the
surface region of the mixture becomes progressively moistened with
biological fluid, successive molecules of drug are "de-adsorbed" to
maintain an effective therapeutic concentration of the drug in the
surrounding tissue over an extended period. Unfortunately, predictable
adsorption and de-adsorption are only practical if the matrix material is
biologically inert which significantly limits the utility of the matrix
itself. That is, the biologically active, ceramic-glass, which is
preferred for bone replacement, does not readily adsorb drugs. Further,
when an insoluble biologically inert material to which drug is absorbed is
implanted in soft tissue, the material is likely to be encapsulated by
tissue to form a cyst.
Biodegradable micro capsules, containing soluble drug or hormone material,
can be prepared which will release material at a constant rate over
measured periods of time. This can be achieved using the property of
biologically active, ceramic-glass to form a slightly alkaline interface
at its exposed surface as apatite is formed. Within the biologically
active ceramic-glass matrix, wetting with biological fluids will occur but
the pH will not change. Microcapsule formulations which are stable at pH
levels below about 8 or 9 and which lyse or release at pH above about 9
are preferred. Drug release is controlled at, and limited to, the site
where apatite is being formed.
FIG. 3a schematically illustrates the material of the present invention
wherein one or more drugs are microencapsulated and the micro capsules are
intimately mixed with finely divided particulate, biologically active
ceramic-glass. Upon placement in a biological environment, e.g., in bone
or soft tissue of a patient, exposure to the biological fluids ruptures
the micro capsules to release the drug into the surrounding tissue.
Exposure and rupture of the micro capsules occurs only at the surface of
the matrix.
Referring to the graph in FIG. 3b, because the rate of release of drug is
proportional to the surface area, maintaining a constant surface area
leads to a constant rate of drug release and generally preferred drug
delivery profile illustrated by the solid line. The drug release profile
of the material of the present invention can be tailored to meet the
preferred delivery profile of a particular drug by varying the exposed
surface area and the composition/thickness of the microencapsulating
material.
Still referring to the graph in FIG. 3b, if the material of the present
invention were implanted into soft tissue in the form of a sphere, a drug
delivery profile illustrated by the dashed line might be achieved as the
sphere of uniform drug concentration continuously decreased in surface
area. However, layers of the material of the present invention impregnated
with varying amounts of drug could be built-up to make an implant with
high drug concentration in the interior of the sphere and progressively
lower concentrations in the outer shells of the sphere. Thus, as the
surface area of the sphere is diminished by biological erosion, the amount
of the drug released is held constant since the concentration of drug is
greater in the interior of the drug delivery sphere. These drug delivery
spheres would provide the stable delivery profile illustrated by the
dash-dot-dash line.
Referring to the schematic diagram in FIG. 4a, by forming biologically
active ceramic-glass in a colloidal block with a nonuniform distribution
of microencapsulated drugs, one could regulate the concentration and
biological sequencing of drugs. Conveniently, nonuniform distribution of
drug in a biologically active ceramic-glass matrix is obtained by building
up layers varying in drug concentration and composition as taught above.
In this illustration, biologically active ceramic-glass has been combined
with a microencapsulated antibiotic and analgesic and two different bone
growth hormones. A higher concentration of antibiotic and analgesic micro
capsules is placed near the surface of the colloid than in its interior.
Thus, higher, stable analgesic and antibiotic concentrations are achieved
immediately after surgery.
As illustrated by the graph of FIG. 4b, at an appropriate time, further
local antibiotic treatment is unnecessary and the concentration of
antibiotic capsules deeper in the colloid is zero. The Type I hormone is
required to initiate infiltration of the matrix with osteoclasts. This
enhances initial remodeling, but if left to continue, this remodeling
would be counter productive. A second growth stimulating hormone (Type II)
is microencapsulated at a layer farther within the colloid. As aqueous
diffusion into the colloid progresses, the high pH is formed deeper within
the colloid, releasing the Type II hormone to sustain the secondary phases
of bone reformation.
Thus, the combination of biologically active ceramic-glass with its
resultant unique pH change in the physiologic environment and
biodegradable microcapsule will result in the delivery of the drug or
hormone-like substances to a surgically defined site. These concentrations
can be regulated to be appropriate for the local tissue requiring
treatment and do not effect distal sites because systematic concentrations
would be minimal. Further, the material can be sequenced. The technique is
appropriate for current and future antibiotics. It is also useful for
local administration of both endocrine and locally acting hormonal
substances. The techniques developed will also serve as delivery methods
for therapies developed through genetic engineering.
Optionally, binding agents may be added to a ceramodrug matrix to enhance
its moldable qualities. A binder can be a material which becomes rigid or
viscous some time after activation. For example, the binder may be a
cement-like material which upon mixing with water or biological fluids
"sets-ups" within a few minutes to a few hours depending on the
applications.
Typically, the matrix material might be stored as finely divided particles.
Just prior to application, the material would be mixed with a
physiologically comparable substance, e.g., buffered, sterile water or
normal saline, to form a thick paste, which would be placed in the area
where the bone was to be reconstructed. Upon contact with physiological
fluids, the material would become rigid or semi-rigid due to surface
interactions with macromolecules.
Alternatively, the material may be supplied as preformed into semi-rigid
shapes, such as strips, rods, spheres, etc., which could be molded or
sculptured to the required shape by the surgeon just prior to implantation
as a bone replacement material. Also, the material could be preformed into
stock or custom shapes closely approximating the shapes of the bone
section to be replaced.
In addition to being physiologically comparable, an acceptable binder
degrades in a physiologically active environment at approximately the same
rate as the rate as the biologically active ceramic-glass when it is being
replaced by bone. The material of the present invention may also
optionally contain preservatives, stabilizers, colorants, and buffers.
Where the drug impregnated biologically active ceramic-glass material is
used solely as drug depot in soft tissue, and not also as a bone
replacement material, it is preferably implanted in a rigid or semi-rigid
form which maintains approximately constant surface area over most of its
effective life. Alternatively, the impregnated biologically active
ceramic-glass matrix material can be placed in a cavity of a solid
material that degrades at a lesser rate than the biologically active
ceramic-glass. For example, the impregnated biologically active
ceramic-glass material might be placed in a thin wall, wide diameter
open-ended cylinder where the exposed surface would be approximately
constant, and consequently, the drug delivery profile would be
approximately constant. The matrix material could also be implanted in the
form of regular or irregular solid, geometric shapes, e.g., thin strips,
spheres, spheroids, etc.
The drug impregnated biologically active ceramic-glass material of the
present invention need not be homogeneous when used as a bone replacement
material. For example, several formulations of matrix material of varying
concentrations and combinations of drug may be added in layers within a
bone cavity. Because the amount of drug delivered is directly proportional
to the exposed surface of the matrix, a typical solid geometric shape,
e.g., a sphere, would deliver progressively less drug as the sphere was
degraded in a biological environment if it were of uniform composition.
Therefore, the concentration of the drug in the matrix is a decreasing
gradient moving from the center of the solid to the surface. The effect of
diminished delivery because of diminished surface area can be compensated
by making the interior of the solid a greater concentration than the
exterior portion.
Particulate, bioactive ceramic glasses in accordance with the present
invention typically have the following composition by weight percentage:
______________________________________
Compound % Compound %
______________________________________
SiO.sub.2 40-60 CaF.sub.2 0-25
CaO 10-30 B.sub.2 O.sub.3
0-10
Na.sub.2 O 10-35 K.sub.2 O 0-8
P.sub.2 O.sub.5
2-8 MgO 0-5
______________________________________
where the total percentage equals 100. The preferred composition of the
bioactive ceramic glass is:
______________________________________
Compound
%
______________________________________
SiO.sub.2
45.0
CaO 24.5
Na.sub.2 O
24.5
P.sub.2 O.sub.5
6.0
______________________________________
which is commercially available under the trademark Bioglass.RTM. (supplied
by US Biomaterials, One Progress Boulevard, #23, Alachua, Fla., 32615)
The particulate biologically active material used in the present invention
may be prepared according to the methods of the art such as taught in U.S.
Pat. Nos. 4,159,358; 4,234,972; 4,103,002; 4,189,325; 134,171,544;
4,775,646; 4,857,046, and 5,074,916. For example, the raw materials (e.g.,
SiO.sub.2, CaO, Na.sub.2 O and P.sub.2 O.sub.5) are mixed in a Nalgene
(trademark) plastic container on a ball mill for four hours. The mix is
then melted in a platinum crucible at 1350.degree. C. and homogenized for
24 hours. The molten glass is poured into distilled, deionized water to
produce a glass frit. The frit is ground in a mortar and pestle and passed
through ASTM sieves to produce the required particle size range.
The preferred particle size range for the bioactive glass is site and use
dependent. Particle sizes less than about 1000 microns and greater than
about 2 microns can also be used. Particles of such a small size range
generally provide for the advantages of the present invention but do not
elicit any undesirable immune response.
Examples of antibiotics useful with the present invention include, but are
not limited to: ampicillin, chloramphenicol, chlortetracycline,
clindamycin, erythromycin, gramicidin, gentamicin, mupiroicin, neomycin,
polymyxin B, bacitracin, silver sulfadiazine, tetracycline and
chlortetracycline. Those of ordinary skill in the art will appreciate that
there are other appropriate topical antibiotics, such as those listed in
U.S.P.D., which may also be used in the present invention.
Examples of hormones and other related drugs useful with the present
invention include, but are not limited to: human growth hormone (hGH),
bone morphogenetic proteins (BMPs) (C.F. Paatsama, S., et al.)
transforming growth factors (TGF-.beta.s), interferons, interleukins,
calcitonin, estrogen and 17-.beta. estradiols. Examples of
anti-inflammatory drugs include, but are not limited to: cortisone,
Nonsteroidal Anti-inflammatory Drugs (NSAIDs), and interleukin 3
inhibitors.
A drug may be microencapsulated and mixed with particulate bone matrix
material. This technique is useful for both biologically inert and
biologically active matrix materials. Biodegradable micro capsules,
containing one or more drugs can be prepared by methods known in the art
(see Microencapsulation: Methods and Industrial Application, ed. by Simon
Benita, Marcel Dekker, Inc. New York, 1996). Particularly useful are
microcapsule formulations which are stable at pH levels below about 9 and
which lyse or release at pH above about 9. By controlling these pH
variations, drug release will be controlled at and limited to the site
where apatite is being formed.
The ceramodrug matrix of the present invention is useful in repairing bone
defects which have been caused by surgical removal due to cancer, lost
bone due to infection or trauma, or lengthening or remodeling of bone
underlying soft tissue. Specific examples include repairing trephine holes
remaining after neurosurgery, bone grafting in periodontal and
maxillofacial surgery and repair of long bones which have been chipped or
shattered as a result of trauma.
Many of the antitumor drugs in current clinical use are cytotoxic materials
which work by killing the malignant cells faster than the normal cells.
When these potent drugs are given systemically, a large number of normal
cells are killed or disabled which often leads to massive, undesirable
side effects. It has long been recognized that localized tumors could best
be treated by delivering a small, but effective, amount of an appropriate
drug close to or, even better, inside the tumor. Preferably, an antitumor
drug, or mixture of drugs, would be delivered directly to the tumor site
to form a high drug concentration in the immediate vicinity of the tumor
with minimal amount reaching the blood stream and being carried throughout
the body. Ideally, the drug would be delivered in a controlled manner over
a period of time.
The ceramodrug matrix of the present invention is well suited for localized
treatment of tumors. The biologically active ceramodrug matrix impregnated
with one or more antitumor drugs can be injected directly into the tumor
or implanted in close proximity to the tumor. The material of the present
invention is especially suited for treatment of malignancies of the bone.
The material of the present invention can be formulated to deliver drugs
systematically where such a mode of delivery is advantageous to the
patient. For example, the ceramodrug matrix may be impregnated with a high
concentration of microencapsulated drug and the drug can be
microencapsulated by a material that is easily lysed. Further, the
impregnated material can be placed in tissue rich in blood vessels. A low
level, continuous, predictable, systematic delivery method is useful for
hormone replacement therapy, as well as for birth control, and delivery of
antidepressant, antipsychotic and anticonvulsant drugs.
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